Antiepileptic drug monitoring In pregnancy
| ISRCTN | ISRCTN01253916 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN01253916 |
| Secondary identifying numbers | HTA 09/55/38 |
- Submission date
- 02/06/2011
- Registration date
- 07/06/2011
- Last edited
- 09/05/2018
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nervous System Diseases
Plain English Summary
Background and study aims
Many mothers require long-term treatment with drugs to manage epilepsy, called antiepileptic drugs (AEDs). The levels of these drugs in the blood usually fall in pregnancy. This may increase the risk of seizures. Currently, some doctors carry out regular blood tests to check the level of the drugs in the blood in pregnancy. They offer to increase the dose if the levels fall compared to the last level. This is called therapeutic drug monitoring (TDM). Other doctors do not carry out regular blood tests in pregnancy. They only increase the dose if seizures worsen or if they occur for the first time in pregnancy. This is called clinical features monitoring (CFM). This study aims to find the AED monitoring method that is best and safest for seizure control in pregnancy. Currently, there is not enough evidence to strongly recommend one method of monitoring over the other in pregnancy.
Who can participate?
Pregnant women who are known to have epilepsy and are currently on one or more of the following drugs: carbamazepine, lamotrigine, levetiracetam or phenytoin.
What does the study involve?
Participants are seen as usual in a hospital antenatal clinic, every 4 weeks up until 6 weeks after they given birth. They are asked to:
1. Have regular blood tests every 4 weeks to check the drug (AED) levels in their blood until labour or delivery. The blood samples are stored for the lifetime of the trial and for 3 years after the completion of the trial. After this period, the samples are destroyed.
2. Complete a seizure diary throughout their pregnancy and up to 6 weeks after birth to document the type and frequency of any seizures they may experience, including any side effects.
3. Complete questionnaires about general well being (quality of life) at each clinic visit.
4. Provide a sample of blood from the umbilical cord after it has been cut. This will give us information on the level of AED in the babys blood at birth. When the baby is 6 weeks old, at a routine 6-week postnatal appointment, we will assess clinical information about the participant and her baby. Participants and their babies may be requested to attend a long-term follow-up appointment about five years after delivery. Participants can choose whether or not to participate in this visit.
5. Complete a questionnaire about any out of pocket expenses (e.g. transport costs, time lost from work or child care costs) they may have incurred when attending the clinics. This will help us find out about the wider cost implications of the two monitoring methods on the health service.
What are the possible benefits and risks of participating?
As we do not know the best method to monitor drugs in pregnancy, we cannot say if there will be any direct benefit to the participant and/or her baby. However, taking part in this study will help inform decisions about management of pregnant women with epilepsy in the future.
Participants may have side effects related to the type and dose of AED. It is expected that they will continue to take their usual AEDs, as it is less likely for these to be changed during pregnancy. If it is necessary to increase/decrease the dose of AEDs or change them, then the reasons for this will be discussed with the participant and their clinician/nurse in the usual way, giving them the opportunity to discuss concerns about the process.
Where is the study run from?
The study takes place at various joint neurology obstetric antenatal clinics or high-risk clinics at hospitals throughout the United Kingdom, with a total of 41 centres expressing interest or participating.
When is the study starting and how long is it expected to run for?
Patients will be enrolled in the study between November 2011 and October 2013. Follow-up examinations will continue until April 2014.
Who is funding the study?
NIHR Health Technology Assessment Programme (UK)
Who is the main contact?
Prof. Khalid Khan
k.s.khan@qmul.ac.uk
Contact information
Scientific
Women’s Health Research Unit
Centre for Primary Care and Public Health
Blizard Institute
Barts and The London School of Medicine and Dentistry
Yvonne Carter Building
58 Turner Street
London
E1 2AB
United Kingdom
| k.s.khan@qmul.ac.uk |
Study information
| Study design | Multicentre randomised controlled trial within a cohort study and a qualitative study of patient acceptability |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Diagnostic |
| Participant information sheet | Not available in web format, please use contact details to request a patient information sheet |
| Scientific title | AntiEpileptic drug Monitoring in PREgnancy: an evaluation of effectiveness, costeffectiveness and acceptability of monitoring strategies |
| Study acronym | EMPiRE |
| Study hypothesis | Does therapeutic drug monitoring (TDM), among pregnant women with epilepsy on antiepileptic drugs (AEDs), reduce the risk of seizure deterioration compared to clinical features monitoring (CFM) alone? 1. What is the effect of TDM Vs CFM on quality life in pregnant women on anti epileptic drugs? 2. Is there a difference in the total AED exposure between TDM and CFM monitoring strategies? 3. What, if any, is the relationship between level of fall in serum AED levels and seizures? 4. What are the adverse effects of AED exposure on mother and foetus? 5. What are the views and experiences of pregnant women with epilepsy? 6. What is the most cost-effective method of monitoring for the health service? |
| Ethics approval(s) | Coventry & Warwickshire REC approval pending as of 03/06/2011 |
| Condition | Epilepsy in pregnancy |
| Intervention | Relevant neurological and obstetric history will be obtained from pregnant women with epilepsy at booking / antenatal visit. Baseline data will be collected on age, ethnicity, age at first seizure (excluding febrile seizures), seizure frequency over the previous 6 months, seizure types, epilepsy syndrome, aetiology of epilepsy, duration of epilepsy, current AED and dose, baseline AED level, learning difficulty, any neurological signs, school leaving age, educational performance, current employment, previous AED pregnancy exposure, previous pregnancy complications, perinatal outcome, number of children, health of child and educational status of child at the first visit. There are 3 groups - The treatment groups will be clinical features monitoring alone versus therapeutic drug monitoring (for some centres around the UK clinical features monitoring is usual practice whereas in other therapeutic drug monitoring is usual practice). The third group will be participants whose blood AED levels remain stable. Women will be followed up in the usual way every 4 weeks. Serum AED levels will be obtained but results will be kept blinded. Details of seizures, responses to QoL questionnaire and obstetric assessments will be recorded 4 weekly. A seizure diary specially developed for collecting trial data will be obtained but results will be kept blinded. It will provide details of type of seizure, frequency of seizure in the last 4 weeks and any side effects from the medication. The daily dose of AED and any increase will be recorded. The foetus will be evaluated by detailed ultrasound scan at 20 weeks for congenital abnormalities and serial growth scans if fetal growth restriction is suspected. Foetal outcomes will be collected antenatal, at delivery and 6 weeks after delivery. An online data entry system, with appropriate security, will allow physicians, and specialist nurses to enter data directly. |
| Intervention type | Other |
| Primary outcome measure | Time from randomisation to first seizure and time to first tonic clonic seizure throughout pregnancy up to and including six weeks post-delivery. Statistical analysis will take into account the time to each event per woman over the whole period of monitoring. Participants will be asked to document the occurrence of each seizure by frequency and type in a trial specific seizure diary. |
| Secondary outcome measures | Maternal: 1.Neurological 1.1. Percentage of women experiencing seizures who were seizure free in three month prior to consent. Number of seizures per week and number of seizure free days per week throughout pregnancy and up to and including six weeks post delivery 1.2. Serum levels of AED in each trimester, daily dose exposure by trimester, cumulative dose exposure for pregnancy, adverse events as measured by the Liverpool Adverse Events Profile 2. Obstetric Maternal death, mode of delivery, preterm labour, induction of labour, pre eclampsia, antepartum and postpartum haemorrhage, admission to high dependency/ intensive care unit, breast feeding, infection, gestational diabetes mellitus 3. Quality of Life: Epilepsy specific QoL as measured by QOLIE-31, generic QoL as measured by EQ-5D Foetal and neonatal: Major and minor congenital malformation: major congenital malformations defined as structural abnormalities with surgical, medical or cosmetic importance at antenatal or post natal diagnosis. Apgar score at 1 and 5 minutes, admission to neonatal unit, birth weight, head circumference, foetal growth, stillbirths, neonatal deaths, Bayley Scales of Infant Development (BSID). |
| Overall study start date | 01/07/2011 |
| Overall study end date | 31/05/2015 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Female |
| Target number of participants | Target sample=1000, Recruited sample 540 |
| Participant inclusion criteria | 1. Have signed a consent form before undergoing any trial-related activities 2. Have a confirmed viable pregnancy of less than 16 weeks gestation at booking 3. Have a confirmed diagnosis of epilepsy (any syndrome: primary, localised or unclassified) 4. Currently prescribed lamotrigine monotherapy or polytherapy (with carbamazepine, phenytoin or levetiracetam), carbamazepine monotherapy, phenytoin monotherapy or levetiracetam monotherapy 5. Be capable of understanding the information provided, with use of an interpreter if required |
| Participant exclusion criteria | 1. Be beyond 16 weeks gestation at booking 2. Documented non-epileptic seizures in the last 2 years 3. Documented of status epilepticus in the last 12 months 4. A history of alcohol or substance abuse or dependence in the last 2 years 5. Sodium valproate (VPA) monotherapy or polytherapy 6. Non lamotrigine polytherapy 7. A history of poor AED adherence 8. Unable to complete a seizure diary or recall frequency of seizures accurately 9. Have a significant learning disability 10. Participation in any blinded, placebo-controlled trials of investigational medicinal products in pregnancy |
| Recruitment start date | 01/07/2011 |
| Recruitment end date | 31/08/2014 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Centre for Primary Care and Public Health
Blizard Institute
Barts and The London School of Medicine and Dentistry
Yvonne Carter Building
58 Turner Street
London
E1 2AB
United Kingdom
Belfast
BT12 6BA
United Kingdom
Glasgow
G51 4TF
United Kingdom
Edinburgh
EH16 4SA
United Kingdom
Newport
NP20 2UB
United Kingdom
Abergavenny
Monmouthshire
NP7 7EG
United Kingdom
Rhyl
LL18 5UJ
United Kingdom
Morriston
Swansea
SA6 6NL
United Kingdom
Cardiff
South Glamorgan
CF24 0SZ
United Kingdom
Newcastle upon Tyne
NE1 4LP
United Kingdom
Sunderland
SR4 7TP
United Kingdom
Durham
DH1 5TW
United Kingdom
Sheffield
S10 2
United Kingdom
Leeds
LS1 3EX
United Kingdom
Warrington
Cheshire
WA5 1QG
United Kingdom
L8 7SS
United Kingdom
Blackburn
BB2 3HH
United Kingdom
Casterton Avenue
Burnley, Lancashire
BB10 2PQ
United Kingdom
M13 9WL
United Kingdom
Derby
DE22 3NE
United Kingdom
Stafford
ST16 3SA
United Kingdom
ST4 6QG
United Kingdom
Shrewsbury
Shropshire
SY3 8XQ
United Kingdom
Birmingham
B15 2TG
United Kingdom
Birmingham
B18 7QH
United Kingdom
Northampton
NN1 5BD
United Kingdom
-
United Kingdom
Coventry
West Midlands
CV2 2DX
United Kingdom
Worcester
WR5 1DD
United Kingdom
Oxford
OX3 9DU
United Kingdom
Romford
Essex
RM7 0AG
United Kingdom
London
E11 1NR
United Kingdom
London
E13 8SL
United Kingdom
London
E1 1BB
United Kingdom
London
SE1 7EH
United Kingdom
London
SW10 9NH
United Kingdom
London
SW17 0QT
United Kingdom
Chichester
PO19 6SE
United Kingdom
Worthing
West Sussex
BN11 2DH
United Kingdom
Frimley
Surrey
GU16 7UJ
United Kingdom
Brighton
BN2 5BE
United Kingdom
Westcliff-on-Sea
SS0 0RY
United Kingdom
Colchester
CO4 5JL
United Kingdom
Winchester
SO22 5DG
Basingstoke
Hampshire
RG24 9NA
Portsmouth
PO6 3LY
United Kingdom
Southampton
Hampshire
SO16 5YA
United Kingdom
Gloucester
GL1 3NN
United Kingdom
Treliske
Truro, Cornwall
TR1 3LQ
United Kingdom
London
N18 1QX
United Kingdom
Bradford
Yorkshire
BD9 6RJ
United Kingdom
Sponsor information
University/education
Queen Mary Innovation Centre
5 Walden Street
Whitechapel
London
E1 2EF
England
United Kingdom
| sponsorsrep@bartshealth.nhs.uk | |
"ROR" |
https://ror.org/026zzn846 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- NIHR Health Technology Assessment Programme, HTA
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/08/2017 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal in August 2017. |
| IPD sharing plan | The current data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 01/05/2018 | Yes | No |
Editorial Notes
09/05/2018: Publication reference added.
14/06/2017: The overall trial end date has been updated from 31/03/2016 to 31/05/2015. In addition, the IPD sharing statement and publication and dissemination plan have also been added.
02/03/2016: Added Bradford Royal Infirmary as a trial participating centre
01/03/2016: Added 50 trial participating centres to record
10/02/2016: Changed recruitment end date and overall end date from 01/02/2015 to 31/08/2014 and 31/03/2016 respectively. The sponsor email address was changed from gerry.leonard@bartsandthelondon.nhs.uk to sponsorsrep@bartshealth.nhs.uk. The details for both the trial participating centre and contact details were changed from "Centre for Health Sciences,
Barts and The London School of Medicine and Dentistry, 2 Newark Street" to "Women’s Health Research Unit
Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Yvonne Carter Building, 58 Turner Street".
